Assistant: Vicky Brennan
The Hedgehog signaling pathway orchestrates key events in embryonic and post-natal development across the metazoans. Its dysregulation leads to the profound congenital deformities observed in holoprosencephaly and brachydactyly and is responsible for several human cancers, including basal cell carcinoma and juvenile medulloblastoma. Multiple lines of biochemical, cellular, and patient-based data indicate that Hh pathway components use cholesterol and its oxygenated derivatives as currency to communicate with downstream effectors. However, owing to the lack of specific, well-defined cholesterol probes, the precise mechanisms by which these metabolites control Hh pathway activity remain unknown.
Research in the Ondrus group combines chemical synthesis, proteomic and genetic screens, and zebrafish embryology to define how network-level information is patterned in the structures of cholesterol metabolites. By interrogating specific functional and biochemical roles of active sterols in Hh signaling, we seek to advance our understanding of endogenous Hh pathway activity and inform the design of treatments for Hh pathologies.